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Pulmonary Lymphoepithelioma-Like Carcinoma: A Mini-Review

Authors Hu Y, Ren S, Liu Y, Han W, Liu W

Received 6 December 2019

Accepted for publication 30 March 2020

Published 11 May 2020 Volume 2020:13 Pages 3921—3929

DOI https://doi.org/10.2147/OTT.S241337

Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 2

Editor who approved publication: Dr William C. Cho



Yan Hu,1 Siying Ren,2 Yukang Liu,1 Wei Han,1 Wenliang Liu1

1Department of Thoracic Surgery, Second Xiangya Hospital of Central South University, Changsha 410011, People’s Republic of China; 2Department of Respiratory and Critical Care Medicine, Second Xiangya Hospital of Central South University, Changsha 410011, People’s Republic of China

Correspondence: Wenliang Liu
Department of Thoracic Surgery, Second Xiangya Hospital of Central South University, No. 139 Middle Renmin Road, Changsha, People’s Republic of China
Tel +8673185296122
Email [email protected]

Abstract: Pulmonary lymphoepithelioma-like carcinoma (PLELC) is a rare and distinct subtype of non-small-cell lung carcinoma associated with Epstein–Barr virus (EBV) infection. We systematically reviewed the recent research that expands our knowledge about PLELC, with main focus on its genetic profile, tumor-infiltrating environment, PD-L1 expression, circulating EBV-DNA, clinical utility of 18F-FDG PET/CT, and treatment strategy. A low frequency of typical driver mutations and widespread existence of copy number variations was detected in PLELC. Persistent EBV infection may trigger intense infiltration of lymphocytes, representing enhanced tumor immunity and possibly resulting in a better prognosis. Circulating EBV-DNA in the plasma of patients with PLELC may predict disease progression and response to therapy. PLELC is 18F-FDG avid, and 18F-FDG PET may help refine palliation strategies and subsequently improve the prognosis. Most of the reported patients present at early and resectable stage, and surgical resection with curative intent is the preferred approach. There is currently no consensus on the regimen of chemotherapy for patients with advanced stages. EGFR-targeted therapies seem to have no therapeutic effect, and the clinical impact of PD-1/PD-L1 therapy is uncertain but worthy of further research.

Keywords: pulmonary lymphoepithelioma-like carcinoma, genetic profile, EBV infection, PD-L1 expression, tumor inflammatory microenvironment, treatment strategy

Introduction

Pulmonary lymphoepithelioma-like carcinoma (PLELC) is a rare and distinct subtype of non-small-cell lung cancer (NSCLC) associated with Epstein–Barr virus (EBV) that is less reported and not well understood.1 It accounts for ~0.7% of all NSCLC cases and usually affects young, nonsmoking, Asian populations2 and clinical and radiographic manifestations are not pathognomonic.1,3 The tumor has distinct pathologic features which are indistinguishable from those of undifferentiated nasopharyngeal carcinoma and is characterized by poorly differentiated tumor cells with large vesicular nuclei and prominent nucleoli showing syncytial growth patterns along with heavy lymphocytic infiltration.4,5 It has also been reported that PLELC displays nonclassic morphology with little lymphocytic infiltration.6 The tumor is typically positive for CK5/6, EMA, p63 and p40, suggesting squamous cell lineage.7,8 The presence of EBV in the nuclei of tumor cells is essential for the diagnosis, which can be detected by in situ hybridization for EBV-encoded RNA (EBER). The majority of patients with PLELC are detected at early stage and may have better prognosis than other subtypes of NSCLC.2,4

This review is to summarize recent research that expands our knowledge about PLELC, with main focus on its genetic profile, tumor-infiltrating environment, PD-L1 expression, circulating EBV-DNA, clinical utility of 18F-FDG PET/CT, and treatment strategy (see Table 1).

Table 1 Main Findings of the Study

Genetic Profile of PLELC

Several driver mutations have been reported to cause NSCLC.9 Owing to the rarity of PLELC, few previous studies existed investigating its genetic status and association with clinicopathologic characteristics.8,10,11 Epidermal growth factor receptor (EGFR) mutation and anaplastic lymphoma kinase (ALK) rearrangement have been the first well-characterized genetic alterations with corresponding targeted agents that have greatly changed the treatment paradigm of advanced NSCLC.9 Other oncogenic drivers have emerged as novel molecular targets with potential therapeutic implications such as mutations in the gene Kirsten rat sarcoma viral oncogene homolog (KRAS), BRAF, and ROS1 and MET gene amplification.12 An earlier study on the prevalence of EGFR mutations among different histological types of lung cancer demonstrated a low prevalence (1 of 11) of EGFR mutations in PLELC (see Table 2).13 Chang et al showed p53 and EGFR mutations were uncommon in PLELCs.8 In this study, p53 mutations were identified in only 3 of 46 cases (6.5%) and EGFR mutations were observed in 8 of 46 cases (17.4%) with a majority of exon 21 mutations but without L858R. Notably, EGFR mutations were more commonly found in patients with tumor size ≤3 cm.8 Wang et al found that only 1 of 42 cases was observed to harbor EGFR L858R mutations.14 Chang et al, in another study, found that the overall frequency of EGFR alterations was 12.1%.15 Liang et al analyzed EGFR mutations in exons 18, 19, 20, and 21 in 11 patients with PLELC and found that all were wild type.2 Yeh et al demonstrated that EGFR was wild type in all 18 patients in whose information was available.6 Liu et al showed that none of the 32 patients with PLELC had EGFR mutations in exons 19 and 21.10 Fang et al found that EGFR mutation rate was 1.8% (2 of 113).16 Recently, Hong et al explored the landscape of PLELC and confirmed a low degree of typical driver mutations including EGFR, KRAS, and BRAF.17 Although MET mutations were detected in two PLELC patients, none of them belong to the canonical MET exon 14 skipping mutations.17 ALK gene rearrangement is rarely detected in PLELC as well.6,14-16,18 It was absent in most studies. Only one patient of PLELC with EML4-ALK fusion gene was reported recently.19 There were another two studies examining the prevalence of KRAS in PLELC, which failed to identify any KRAS mutated patients.15,16 In addition, one of these studies revealed that no aberrations in BRAF and ROS1 in PLELC could be detected.15 These results above suggested that typical driver mutations in other subtypes of NSCLC might not play an important role in the carcinogenesis of PLELC and EGFR-targeted therapy is not suitable for patients with advanced PLELC.

Table 2 Summary of Molecular Alterations in PLELC

In addition to a low frequency of typical driver mutations, a high prevalence of copy number variations was noted in PLELC.17,20 Xie et al showed that copy number variations were detected in 52% of the patients.20 Interestingly, epigenetic regulation might participate in the process of carcinogenesis as reflected by Xie’s finding that 78% of the patients had mutations in epigenetic regulators.20 Moreover, the frequent overexpression of APOBEC family genes, which participated in innate immune response against virus infections, and frequent loss of type I IFN genes were seen in PLELC, reflecting the complex host-virus counteraction during the process of EBV-associated carcinogenesis.17

Chromosome 11 changes might be closely related to EBV-associated malignancies.17 Chan et al compared the frequency of chromosome 11 copy number gains in three different types of EBV-associated malignancies and revealed that trisomy or polysomy 11 was detected in 6 of 8 PLELC.21 Microsatellite instability (MSI) and loss of heterozygosity (LOH) represent molecular disorders acquired by the cell during neoplastic transformation and have been reported in several cancer types, including lung cancer.22 Dacic et al found that MSI was detected in 2 of 7 PLELC cases and LOH was identified in 3 of 7 PLELC.23 Relative higher frequency of LOH suggested inactivation of tumor suppresser gene in chromosome 5q23 might play a role in PLELC tumorigenesis.23

Tumor Inflammatory Microenvironment of PLELC

PLELC is a tumor with distinct morphologic features characterized by an undifferentiated malignant epithelial neoplasm with a markedly prominent lymphoid infiltrate.24 Few studies explored the mechanism for lymphoid infiltration in the tumor stroma. Whether EBV triggered tumor-infiltrating lymphocytes (TILs) and the immunophenotype and antigen specificity of TILs in PLELC remain to be determined. Kobayashi et al found that tumor-infiltrating lymphocytes in EBV-positive PLELC were predominantly CD8+ and T cell intracytoplasmic antigen (TIA-1)+ cytotoxic T cells with closely linked with HLA-DR+ PLELC cells.25 Chang et al reviewed the histopathology of 23 cases of PLELC and indicated that all of their cases showed prominent infiltration of CD8+ lymphocytes in the tumor cell nests and the surrounding stroma.26 The antigen specificity of these CD8+ lymphocytes is not clear. The accumulation of these CD8+ lymphocytes with the cell-to-cell contact to tumor cells suggested that these CD8+ lymphocytes might be specific to tumor cell antigens coded either by EBV or EBV-induced cellular genes.27 Kasai et al examined the immunophenotype of TILs of two cases of EBV-positive PLELC and found the majority of TILs were cytotoxic T lymphocytes (CTL) in the resting state due to the findings of these TILs labeling with both CD8 and TIA-1 but not with granzyme-B.28 They argued that local inhibition of EBV-specific CTL response such as T-cell anergy might be responsible for the lack of CTL activation at the tumor site.29 TILs have been shown to be related to improved prognosis in certain types of cancer, including NSCLC.30,31 Based on the current literature, we believe that persistent EBV infection in PLELC triggers intense infiltration of lymphocytes, whether activated or not, representing enhanced tumor immunity and possibly resulting in a better prognosis. Recently, Yeh et al quantitatively evaluated the tumor lymphocytic infiltration of 28 cases of PLELC via anti-CD45 staining.6 Interestingly, lymphocytic infiltration pattern in PLELC constituted a wide and continuous spectrum. Larger tumor size, higher SUVmax, and shorter recurrence-free survival in CD45-low group compared to CD45-high group further supported the notion that high lymphocytic infiltration is associated with improved patient outcomes.31,32

In addition to lymphocytes, macrophages have also been detected in significant numbers in NSCLC, being likely to be important determinant of both prognosis and response to therapy.3335 Upon influence of various stimuli in the tumor microenvironment, tumor-associated macrophages (TAMs) interact with tumor cells to develop into a tumor-inhibitory or tumor-promoting phenotype.33 The majority of TAMs are believed to be recruited from peripheral blood monocytes through a chemotactic gradient generated by tumor-derived chemotactic peptides.36 Wong et al reveal that compared with conventional NSCLC, the TAMs infiltrate was more abundant and showed a closer proximity to the MCP-1-expressing tumor cells in PLELC.37 Recruitment of TAMs mediated by MCP-1 from adjacent tumor cells of PLELC might promote tumor development through the elevation of survival and propagation of EBV. Furthermore, Wang et al showed significant expression of TAMs in PLELC and correlated with poor prognosis.38 Moreover, elevated pretreatment monocyte-to-lymphocyte ratio (MLR) was shown to be associated with poor prognosis in patients of PLELC. It seems that TAMs act as a tumor-inhibitor in the tumor microenvironment of PLELC, but further investigations are warranted.

PD-L1 Expression in PLELC and Its Prognostic Value

Tumor immune evasion is an emerging hallmark of cancer.39 One possible underlying mechanism might be that cancer co-opts inhibitory pathways such as the programmed cell death-1 (PD-1) pathway.40 Lung cancer has been detected to express programmed cell death-1 ligand (PD-L1) on their cell surface, which is a known ligand of the PD-1 receptor on T cells.41 This pathway causes T-cell exhaustion or apoptosis and subsequent immune escape.42,43 Novel PD-1/PD-L1 monoclonal antibodies can block either of these two binding sites, thereby restoring function of exhausted T cells.44 These immune-checkpoint inhibitors not only show preclinical activity in NSCLC, but have already entered clinical practice in advanced NSCLC either as monotherapy or in combination with chemotherapy, changing the therapeutic landscape of non-oncogene addicted patients.45 Evidences revealed that 63.3–75.8% of the PLELC, which usually lacked common driver gene mutations like EGFR, showed PD-L1 positivity in tumor cells.15,16,46,47 This proportion was higher than that in lung adenocarcinoma (13.5–53.6%) as shown in a meta-analysis by Zhang et al.48 In view of the different EGFR mutation profiles reported in PLELC and lung adenocarcinoma, the association between frequent PD-L1 expression and EGFR wide-type status seemed plausible.48 Given the finding that PLELC is strongly associated with EBV infection, PD-L1 induction dependent upon constitutive expression of the EBV-coded gene products, such as latent membrane protein-1 (LMP-1) is intuitive.49,50 Moreover, Hong et al revealed the relationship between CD274 gene amplification and PD-L1 overexpression in PLELC, but how the underlying mechanism remained unknown.17

With respect to the prognostic significance of positive PD-L1 in tumor cells of PLELC, no consensus has been reached. Yu et al observed that PD-L1 (+) in tumor cells predicted longer DFS in patients with PLELC,46 which was consistent with Jiang et al’s results.47 By contrary, Fang et al reported that PD-L1 high expression was associated with impaired DFS in resectable PLELC.16 Moreover, no prognostic implication of PD-L1 frequent positivity in tumor cells of PLELC was reported in Chang et al’s study.15

Association of EBV Infection and PLELC Occurrence and Prognostic Value of Circulating EBV DNA in PLELC

Because of the PLELC’s close association with EBV infection, the 2015 World Health Organization classification requires the presence of EBV within the nuclei of the neoplastic cells in order to make its diagnosis.24 The EBV is often detected in pulmonary LELC occurring in Asian patients,2,3,6,8,10,14,51-54 but rarely detected or even undetected in other types of lung cancer such as adenocarcinoma, squamous cell carcinoma, and SCLC.55,56 Negative expression of EBV in patients with PLELC from Western countries suggests EBV as not an indispensable factor for the development of PLELC.5659

Previous studies have measured circulating EBV DNA in the plasma of patients with pulmonary LELC and suggested its role for monitoring response to therapy.60,61 Xie et al demonstrated variation of plasma EBV DNA in two patients treated with chemotherapy and/or radiotherapy was consistent with their clinical course.54 Xie et al performed a prospective multicenter study in Southern China investigating the association between baseline EBV DNA and OS and disease-free survival (DFS) in a total of 429 patients with pulmonary LELC and showed that baseline EBV DNA copy of at least 4000 copies/mL predicted disease recurrence and poorer survival among patients with early- or advanced-stage pulmonary LELC.62 Through sequential blood draw, they found that plasma EBV DNA frequently preceded disease progression during posttherapy follow-up. Moreover, patients with persistently detectable plasma EBV DNA after radial resection had significantly worse OS and DFS than did those with EBV DNA after surgery.62 Moreover, Lin et al reported that patients with high baseline EBV DNA exhibited significantly shorter PFS and OS than those with low baseline EBV DNA.63 The above findings further supported an oncogenic role of EBV in Asian patients of pulmonary LELC.

Clinical Role of 18F-FDG PET/CT in PLELC

18F-FDG PET/CT is an anatomo-metabolic imaging modality that has recently been introduced to clinical practice and has been recommended by the National Comprehensive Cancer Network to use for routine staging of NSCLC.64,65 The clinical utility of 18F-FDG PET/CT in PLELC remains unknown. Few case reports and retrospective studies described the 18F-FDG avidity of PLELC and found all cases were 18F-FDG avid with a wide range of reported maximum standardized uptake values (SUVmax) ranging from 1.7 to 34.5.6671 A small case series by Chan et al for the first time found that 18F-FDG PET/CT contributed to accurate evaluation of disease staging, treatment response as well as disease recurrence of PLELC.71 Recently, Su et al identified that pretreatment 18F-FDG PET as independently associated with a better OS in patients with PLELC.70 In their study, 18F-FDG PET led to an upstaging in 28.6% of patients with CT-defined stages III-IVa. Intuitively, 18F-FDG PET may help refine palliation strategies and subsequently improve the prognosis.70

Treatment Strategy of PLELC

No clinical practice guideline tailored for PLELC exists owing to its rarity. The treatment of PLELC is the same as with other NSCLC. Most of the reported patients present at early and resectable stage and surgical resection with curative intent is the preferred approach.2 Surgery with adjuvant chemotherapy is recommended by some authors for the patients with stage IIIa for better prognosis.2,72,73 PLELC is reported to be chemosensitive and radiosensitive and multimodality treatment including chemotherapy and/or radiotherapy may play important roles in advanced stage or metastatic PLELC.7476 More importantly, patients with locally advanced stage PLELC may benefit from a more aggressive multimodality approach.70,73

There is currently no consensus on the regimen of chemotherapy for patients with advanced PLELC.1,63 Most of the previous reports on choice of chemotherapy regimen were based on small case series and retrospective studies.1,73,77 5-FU plus cisplatin or 5-FU-based chemotherapy was used in some patients before 2002. Platinum-based doublet chemotherapy was considered the standard regimen for NSCLC after 2002.74 Xie et al reported two cases of advanced PLELC responding well to chemotherapy (paclitaxel plus carboplatin) and chemotherapy (docetaxel plus cisplatin) with radiotherapy, respectively.54 Lin et al reported that 83.3% of the patients treated with palliative chemotherapy with docetaxel and cisplatin gained partial response (10 of 12 patients).72 Liang et al demonstrated that PLELC was sensitive to paclitaxel-based or docetaxel-based regimen.2 Qin et al explored the optimal regimen of chemotherapy for advanced stage PLELC and revealed that patients treated with paclitaxel plus platinum or gemcitabine plus platinum responded more favorably than that with pemetrexed plus platinum.1 Hong et al demonstrated that gemcitabine plus platinum significantly improved objective response rate and progression-free survival compared to pemetrexed plus platinum as first-line treatment of metastatic PLELC.17 Recently, Lin et al found that gemcitabine plus platinum achieved higher response rate and longer median PFS as compared to taxanes plus platinum or pemetrexed plus platinum.63 Besides, Ho et al reported capecitabine monotherapy controlled disease progression in three of five patients with advanced or metastatic PLELC, suggesting the antitumor potential of capecitabine-containing chemotherapy regimen in PLELC.78

Cumulative toxicities induced by the long-term use of conventional chemotherapy propel the practitioners to choose other treatment approaches, such as EGFR-targeted therapy and immunotherapy.76 Targeted therapies are believed to be not very useful due to the lack of actionable mutations.8,10 Previous literature failed to demonstrate the obvious therapeutic effect of EGFR-targeted therapies towards PLELC.1,2,8,10,14,74 Although high expression of PD-L1 in PLELC provides a rationale for implementation of PD-l/PD-L1 monoclonal antibodies, the clinical impact of these agents in PLELC has only been reported in limited case reports (see Table 3).77,79-82 Among them, Kumar et al reported 2 cases of advanced stage PLELC progressed despite multiple lines of chemotherapy, but responded favorably to nivolumab, a PD-1 inhibitor.81 Darasson et al demonstrated a case of a partial response and clinical improvement after pseudoprogression in a patient of PLELC treated with nivolumab after progression using 5 cycles of chemotherapy.80 Narayanan et al presented a case of PLELC responding favorably to blockage with a PD-L1 antibody, atezolizumab.79 Qiu et al described a case of PLELC responding well to nivolumab, manifesting as dramatic decline of tumor burden and serum tumor markers.82 By contrast, Kim et al reported a case of chemotherapy-refractory PLELC showing rapid progression with second-line nivolumab.77 Undoubtedly, a clinical trial testing PD-1/PD-L1 therapy was warranted before this line of treatment could be suggested as a new standard of care for advanced PLELC.

Table 3 Case Reports of PLELC Treatment with Immune-Checkpoint Inhibitors

Conclusion

Pulmonary lymphoepithelioma-like carcinoma is a rare and distinct subtype of non-small-cell lung cancer (NSCLC) associated with Epstein–Barr virus (EBV) infection. EGFR mutation and ALK rearrangements are not commonly detected in PLELC. Persistent EBV infection may trigger intense infiltration of lymphocytes, representing enhanced tumor immunity and possibly resulting in a better prognosis. Circulating EBV-DNA in the plasma of patients with PLELC may predict disease progression and response to therapy. PLELC is 18F-FDG avid and 18F-FDG PET may help refine palliation strategies and subsequently improved the prognosis. Most of the reported patients present at early and resectable stage and surgical resection with curative intent is the preferred approach. There is currently no consensus on the regimen of chemotherapy. EGFR-targeted therapies seem to have no therapeutic effect and the clinical impact of PD-1/PD-L1 therapy is uncertain, but worthy of further research.

Abbreviations

PLELC, pulmonary lymphoepithelioma-like carcinoma; EBV, Epstein–Barr virus; NSCLC, non-small-cell lung cancer; EBER, EBV-encoded RNA; EGFR, epidermal growth factor receptor; ALK, anaplastic lymphoma kinase; KRAS, Kirsten rat sarcoma viral oncogene homolog; MSI, microsatellite instability; LOH, loss of heterozygosity; TILs, tumor-infiltrating lymphocytes; TIA-1, T cell intracytoplasmic antigen; CTL, cytotoxic T lymphocytes; TAMs, tumor-associated macrophages; MLR, monocyte-to-lymphocyte ratio; PD-1, programmed cell death-1; PD-L1, programmed cell death-1 ligand; LMP-1, latent membrane protein-1; DFS, disease-free survival.

Funding

The work was supported by National Natural Science Foundation of China (81700070 to SR), the Hunan Province Natural Science Foundation of China (2019JJ30038 to SR) and the Hunan Province Health Department Research Fund (B2018-0541 to SR).

Disclosure

The authors report no conflicts of interest in this work.

References

1. Qin Y, Xie G, Xie X, et al. Clinical features and prognosis of pulmonary lymphoepithelioma-like carcinoma: summary of eighty-five cases. Clin Lung Cancer. 2019;20(3):e329–e337. doi:10.1016/j.cllc.2018.12.014

2. Liang Y, Wang L, Zhu Y, et al. Primary pulmonary lymphoepithelioma-like carcinoma: fifty-two patients with long-term follow-up. Cancer. 2012;118(19):4748–4758. doi:10.1002/cncr.27452

3. Mo Y, Shen J, Zhang Y, et al. Primary lymphoepithelioma-like carcinoma of the lung: distinct computed tomography features and associated clinical outcomes. J Thorac Imaging. 2014;29(4):246–251. doi:10.1097/RTI.0000000000000070

4. Han AJ, Xiong M, Gu YY, Lin SX, Xiong M. Lymphoepithelioma-like carcinoma of the lung with a better prognosis. A clinicopathologic study of 32 cases. Am J Clin Pathol. 2001;115(6):841–850. doi:10.1309/BUAN-BGFW-69U9-C3H8

5. Chan JK, Hui PK, Tsang WY, et al. Primary lymphoepithelioma-like carcinoma of the lung. A clinicopathologic study of 11 cases. Cancer. 1995;76(3):413–422. doi:10.1002/1097-0142(19950801)76:3<413::AID-CNCR2820760311>3.0.CO;2-X

6. Yeh YC, Kao HL, Lee KL, Wu MH, Ho HL, Chou TY. Epstein-Barr virus-associated pulmonary carcinoma: proposing an alternative term and expanding the histologic spectrum of lymphoepithelioma-like carcinoma of the lung. Am J Surg Pathol. 2019;43(2):211–219. doi:10.1097/PAS.0000000000001173

7. Jiang WY, Wang R, Pan XF, et al. Clinicopathological features and prognosis of primary pulmonary lymphoepithelioma-like carcinoma. J Thorac Dis. 2016;8(9):2610–2616. doi:10.21037/jtd.2016.08.40

8. Chang YL, Wu CT, Shih JY, Lee YC. Unique p53 and epidermal growth factor receptor gene mutation status in 46 pulmonary lymphoepithelioma-like carcinomas. Cancer Sci. 2011;102(1):282–287. doi:10.1111/j.1349-7006.2010.01768.x

9. Hill A, Gupta R, Zhao D, Vankina R, Amanam I, Salgia R. Targeted therapies in non-small-cell lung cancer. Cancer Treat Res. 2019;178:3–43.

10. Liu Q, Ma G, Yang H, et al. Lack of epidermal growth factor receptor gene mutations in exons 19 and 21 in primary lymphoepithelioma-like carcinoma of the lung. Thorac Cancer. 2014;5(1):63–67. doi:10.1111/1759-7714.12060

11. Tong JH, Yeung SF, Chan AW, et al. MET amplification and Exon 14 splice site mutation define unique molecular subgroups of non-small cell lung carcinoma with poor prognosis. Clin Cancer Res. 2016;22(12):3048–3056. doi:10.1158/1078-0432.CCR-15-2061

12. Park SJ, More S, Murtuza A, Woodward BD, Husain H. New targets in non-small cell lung cancer. Hematol Oncol Clin North Am. 2017;31(1):113–129. doi:10.1016/j.hoc.2016.08.010

13. Tam IY, Chung LP, Suen WS, et al. Distinct epidermal growth factor receptor and KRAS mutation patterns in non-small cell lung cancer patients with different tobacco exposure and clinicopathologic features. Clin Cancer Res. 2006;12(5):1647–1653. doi:10.1158/1078-0432.CCR-05-1981

14. Wang L, Lin Y, Cai Q, et al. Detection of rearrangement of anaplastic lymphoma kinase (ALK) and mutation of epidermal growth factor receptor (EGFR) in primary pulmonary lymphoepithelioma-like carcinoma. J Thorac Dis. 2015;7(9):1556–1562. doi:10.3978/j.issn.2072-1439.2015.05.11

15. Chang YL, Yang CY, Lin MW, Wu CT, Yang PC. PD-L1 is highly expressed in lung lymphoepithelioma-like carcinoma: a potential rationale for immunotherapy. Lung Cancer. 2015;88(3):254–259. doi:10.1016/j.lungcan.2015.03.017

16. Fang W, Hong S, Chen N, et al. PD-L1 is remarkably over-expressed in EBV-associated pulmonary lymphoepithelioma-like carcinoma and related to poor disease-free survival. Oncotarget. 2015;6(32):33019–33032.

17. Hong S, Liu D, Luo S, et al. The genomic landscape of Epstein-Barr virus-associated pulmonary lymphoepithelioma-like carcinoma. Nat Commun. 2019;10(1):3108. doi:10.1038/s41467-019-10902-w

18. Wong DW, Leung EL, So KK, et al. The EML4-ALK fusion gene is involved in various histologic types of lung cancers from nonsmokers with wild-type EGFR and KRAS. Cancer. 2009;115(8):1723–1733. doi:10.1002/cncr.24181

19. Ose N, Kawai T, Ishida D, Kobori Y, Takeuchi Y, Senba H. Pulmonary lymphoepithelioma-like carcinoma with echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK) fusion gene. Respirol Case Rep. 2016;4(6):e00200. doi:10.1002/rcr2.200

20. Xie Z, Liu L, Lin X, et al. A multicenter analysis of genomic profiles and PD-L1 expression of primary lymphoepithelioma-like carcinoma of the lung. Mod Pathol. 2019.

21. Chan WY, Chan AB, Liu AY, Chow JH, Ng EK, Chung SS. Chromosome 11 copy number gains and Epstein-Barr virus-associated malignancies. Diagn Mol Pathol. 2001;10(4):223–227. doi:10.1097/00019606-200112000-00003

22. Shen C, Wang X, Tian L, Che G. Microsatellite alteration in multiple primary lung cancer. J Thorac Dis. 2014;6(10):1499–1505. doi:10.3978/j.issn.2072-1439.2014.09.14

23. Dacic S, Lomago D, Hunt JL, Sepulveda A, Yousem SA. Microsatellite instability is uncommon in lymphoepithelioma-like carcinoma of the lung. Am J Clin Pathol. 2007;127(2):282–286. doi:10.1309/CRCU356U7146YC31

24. Sathirareuangchai S, Hirata K. Pulmonary lymphoepithelioma-like carcinoma. Arch Pathol Lab Med. 2019;143(8):1027–1030. doi:10.5858/arpa.2018-0149-RS

25. Kobayashi M, Ito M, Sano K, Honda T, Nakayama J. Pulmonary lymphoepithelioma-like carcinoma: predominant infiltration of tumor-associated cytotoxic T lymphocytes might represent the enhanced tumor immunity. Int Med. 2004;43(4):323–326. doi:10.2169/internalmedicine.43.323

26. Chang YL, Wu CT, Shih JY, Lee YC. New aspects in clinicopathologic and oncogene studies of 23 pulmonary lymphoepithelioma-like carcinomas. Am J Surg Pathol. 2002;26(6):715–723. doi:10.1097/00000478-200206000-00004

27. Saiki Y, Ohtani H, Naito Y, Miyazawa M, Nagura H. Immunophenotypic characterization of Epstein-Barr virus-associated gastric carcinoma: massive infiltration by proliferating CD8+ T-lymphocytes. Lab Invest. 1996;75(1):67–76.

28. Kasai K, Kon S, Sato N, et al. Case report of lymphoepithelioma-like carcinoma of the lung–lymphoid population consisting of cytotoxic T cells in resting state. Pathol Res Pract. 1999;195(11):773–779. doi:10.1016/S0344-0338(99)80120-4

29. Frisan T, Sjoberg J, Dolcetti R, et al. Local suppression of Epstein-Barr virus (EBV)-specific cytotoxicity in biopsies of EBV-positive Hodgkin’s disease. Blood. 1995;86(4):1493–1501. doi:10.1182/blood.V86.4.1493.bloodjournal8641493

30. Badalamenti G, Fanale D, Incorvaia L, et al. Role of tumor-infiltrating lymphocytes in patients with solid tumors: can a drop dig a stone? Cell Immunol. 2018.

31. Bremnes RM, Busund LT, Kilvaer TL, et al. The role of tumor-infiltrating lymphocytes in development, progression, and prognosis of non-small cell lung cancer. J Thorac Oncol. 2016;11(6):789–800. doi:10.1016/j.jtho.2016.01.015

32. Sarraf KM, Belcher E, Raevsky E, Nicholson AG, Goldstraw P, Lim E. Neutrophil/lymphocyte ratio and its association with survival after complete resection in non-small cell lung cancer. J Thorac Cardiovasc Surg. 2009;137(2):425–428. doi:10.1016/j.jtcvs.2008.05.046

33. Jackute J, Zemaitis M, Pranys D, et al. Distribution of M1 and M2 macrophages in tumor islets and stroma in relation to prognosis of non-small cell lung cancer. BMC Immunol. 2018;19(1):3. doi:10.1186/s12865-018-0241-4

34. Kataki A, Scheid P, Piet M, et al. Tumor infiltrating lymphocytes and macrophages have a potential dual role in lung cancer by supporting both host-defense and tumor progression. J Lab Clin Med. 2002;140(5):320–328. doi:10.1067/mlc.2002.128317

35. Kawai O, Ishii G, Kubota K, et al. Predominant infiltration of macrophages and CD8(+) T Cells in cancer nests is a significant predictor of survival in stage IV nonsmall cell lung cancer. Cancer. 2008;113(6):1387–1395. doi:10.1002/cncr.23712

36. Bottazzi B, Polentarutti N, Acero R, et al. Regulation of the macrophage content of neoplasms by chemoattractants. Science. 1983;220(4593):210–212. doi:10.1126/science.6828888

37. Wong MP, Cheung KN, Yuen ST, et al. Monocyte chemoattractant protein-1 (MCP-1) expression in primary lymphoepithelioma-like carcinomas (LELCs) of the lung. J Pathol. 1998;186(4):372–377. doi:10.1002/(SICI)1096-9896(199812)186:4<372::AID-PATH204>3.0.CO;2-8

38. Wang L, Long W, Li PF, Lin YB, Liang Y. An elevated peripheral blood monocyte-to-lymphocyte ratio predicts poor prognosis in patients with primary pulmonary lymphoepithelioma-like carcinoma. PLoS One. 2015;10(5):e0126269. doi:10.1371/journal.pone.0126269

39. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646–674. doi:10.1016/j.cell.2011.02.013

40. Brahmer JR. Harnessing the immune system for the treatment of non-small-cell lung cancer. J clin oncol. 2013;31(8):1021–1028. doi:10.1200/JCO.2012.45.8703

41. Buttner R, Gosney JR, Skov BG, et al. Programmed death-ligand 1 Immunohistochemistry testing: a review of analytical assays and clinical implementation in non-small-cell lung cancer. J clin oncol. 2017;35(34):3867–3876. doi:10.1200/JCO.2017.74.7642

42. Chen L. Co-inhibitory molecules of the B7-CD28 family in the control of T-cell immunity. Nat Rev Immunol. 2004;4(5):336–347. doi:10.1038/nri1349

43. Freeman GJ, Long AJ, Iwai Y, et al. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med. 2000;192(7):1027–1034. doi:10.1084/jem.192.7.1027

44. Brahmer JR, Tykodi SS, Chow LQ, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med. 2012;366(26):2455–2465. doi:10.1056/NEJMoa1200694

45. Russo A, Franchina T, Ricciardi GRR, et al. The changing scenario of 1(st) line therapy in non-oncogene addicted NSCLCs in the era of immunotherapy. Crit Rev Oncol Hematol. 2018;130:1–12. doi:10.1016/j.critrevonc.2018.06.007

46. Yu XY, Zhang XW, Wang F, et al. Correlation and prognostic significance of PD-L1 and P53 expression in resected primary pulmonary lymphoepithelioma-like carcinoma. J Thorac Dis. 2018;10(3):1891–1902. doi:10.21037/jtd.2018.03.14

47. Jiang L, Wang L, Li PF, et al. Positive expression of programmed death ligand-1 correlates with superior outcomes and might be a therapeutic target in primary pulmonary lymphoepithelioma-like carcinoma. Oncol Targets Ther. 2015;8:1451–1457. doi:10.2147/OTT.S84234

48. Zhang M, Li G, Wang Y, et al. PD-L1 expression in lung cancer and its correlation with driver mutations: a meta-analysis. Sci Rep. 2017;7(1):10255. doi:10.1038/s41598-017-10925-7

49. Green MR, Rodig S, Juszczynski P, et al. Constitutive AP-1 activity and EBV infection induce PD-L1 in Hodgkin lymphomas and posttransplant lymphoproliferative disorders: implications for targeted therapy. Clin Cancer Res. 2012;18(6):1611–1618. doi:10.1158/1078-0432.CCR-11-1942

50. Fang W, Zhang J, Hong S, et al. EBV-driven LMP1 and IFN-gamma up-regulate PD-L1 in nasopharyngeal carcinoma: implications for oncotargeted therapy. Oncotarget. 2014;5(23):12189–12202. doi:10.18632/oncotarget.2608

51. Lin L, Lin T, Zeng B. Primary lymphoepithelioma-like carcinoma of the lung: an unusual cancer and clinical outcomes of 14 patients. Oncol Lett. 2017;14(3):3110–3116. doi:10.3892/ol.2017.6510

52. Lin Z, Situ D, Chang X, et al. Surgical treatment for primary pulmonary lymphoepithelioma-like carcinoma. Interact Cardiovasc Thorac Surg. 2016;23(1):41–46. doi:10.1093/icvts/ivw064

53. Tanaka S, Chen F, Date H. Pulmonary lymphoepithelioma-like carcinoma with rapid progression. Gen Thorac Cardiovasc Surg. 2012;60(3):164–167. doi:10.1007/s11748-011-0789-x

54. Xie C, Xu X, Wu B, Yang KY, Huang J. Primary pulmonary lymphoepithelioma-like carcinoma in non-endemic region: a case report and literature review. Medicine. 2018;97(8):e9976. doi:10.1097/MD.0000000000009976

55. Chu PG, Cerilli L, Chen YY, Mills SE, Weiss LM. Epstein-Barr virus plays no role in the tumorigenesis of small-cell carcinoma of the lung. Mod Pathol. 2004;17(2):158–164. doi:10.1038/modpathol.3800024

56. Gomez-Roman JJ, Martinez MN, Fernandez SL, Val-Bernal JF. Epstein-Barr virus-associated adenocarcinomas and squamous-cell lung carcinomas. Mod Pathol. 2009;22(4):530–537. doi:10.1038/modpathol.2009.7

57. Barroso A, Nogueira R, Lencastre H, Seada J, Parente B. Primary lymphoepithelioma-like carcinoma of the lung. Lung Cancer. 2000;28(1):69–74. doi:10.1016/S0169-5002(99)00126-9

58. Castro CY, Ostrowski ML, Barrios R, et al. Relationship between Epstein-Barr virus and lymphoepithelioma-like carcinoma of the lung: a clinicopathologic study of 6 cases and review of the literature. Hum Pathol. 2001;32(8):863–872. doi:10.1053/hupa.2001.26457

59. Yener NA, Balikci A, Cubuk R, Midi A, Orki A, Eren Topkaya A. Primary lymphoepithelioma-like carcinoma of the lung: report of a rare case and review of the literature. Turk Patoloji Derg. 2012;28(3):286–289. doi:10.5146/tjpath.2012.01139

60. Ngan RK, Yip TT, Cheng WW, et al. Circulating Epstein-Barr virus DNA in serum of patients with lymphoepithelioma-like carcinoma of the lung: a potential surrogate marker for monitoring disease. Clin Cancer Res. 2002;8(4):986–994.

61. Ngan RK, Yip TT, Cheng WW, et al. Clinical role of circulating Epstein-Barr virus DNA as a tumor marker in lymphoepithelioma-like carcinoma of the lung. Ann N Y Acad Sci. 2004;1022:263–270. doi:10.1196/annals.1318.041

62. Xie M, Wu X, Wang F, et al. Clinical significance of plasma Epstein-Barr Virus DNA in Pulmonary lymphoepithelioma-like carcinoma (LELC) patients. J Thorac Oncol. 2018;13(2):218–227. doi:10.1016/j.jtho.2017.10.031

63. Lin Z, Fu S, Zhou Y, et al. First-line platinum-based chemotherapy and survival outcomes in locally advanced or metastatic pulmonary lymphoepithelioma-like carcinoma. Lung Cancer. 2019;137:100–107. doi:10.1016/j.lungcan.2019.09.007

64. De Wever W, Stroobants S, Coolen J, Verschakelen JA. Integrated PET/CT in the staging of nonsmall cell lung cancer: technical aspects and clinical integration. Eur Respir J. 2009;33(1):201–212. doi:10.1183/09031936.00035108

65. Paesmans M, Berghmans T, Dusart M, et al. Primary tumor standardized uptake value measured on fluorodeoxyglucose positron emission tomography is of prognostic value for survival in non-small cell lung cancer: update of a systematic review and meta-analysis by the European Lung Cancer Working Party for the International Association for the Study of Lung Cancer Staging Project. J Thorac Oncol. 2010;5(5):612–619. doi:10.1097/JTO.0b013e3181d0a4f5

66. Chan JKI, Tai WM, Wen JM. Collision of lymphoepithelioma-like carcinoma and adenocarcinoma of the lung: a case report. Clin Respir J. 2017;11(6):1052–1056. doi:10.1111/crj.12404

67. Shen DH, Cheng CY, Lin LF, Gao HW, Cheng YL, Chen CY. Conversion from FDG-negative to -positive during follow-up in a rare case of pulmonary lymphoepithelioma-like carcinoma. Clin Nucl Med. 2012;37(7):679–681. doi:10.1097/RLU.0b013e31823ea953

68. Dong A, Zhang J, Wang Y, Zhai Z, Zuo C. FDG PET/CT in primary pulmonary lymphoepithelioma-like carcinoma. Clin Nucl Med. 2015;40(2):134–137. doi:10.1097/RLU.0000000000000301

69. Aktas GE, Can N, Demir SS, Sarikaya A. Primary pulmonary lymphoepithelioma-like carcinoma on FDG PET/CT. Nucl Med Mol Imaging. 2017;51(1):88–92. doi:10.1007/s13139-016-0428-7

70. Su TP, Ho KC, Wang CW, et al. Prognostic value and clinical impact of pretreatment FDG PET in pulmonary lymphoepithelioma-like carcinoma. Clin Nucl Med. 2019;44(2):e68–e75. doi:10.1097/RLU.0000000000002371

71. Chan HY, Tsoi A, Wong MP, Ho JC, Lee EY. Utility of 18F-FDG PET/CT in the assessment of lymphoepithelioma-like carcinoma. Nucl Med Commun. 2016;37(5):437–445. doi:10.1097/MNM.0000000000000475

72. Lin CY, Chen YJ, Hsieh MH, Wang CW, Fang YF. Advanced primary pulmonary lymphoepithelioma-like carcinoma: clinical manifestations, treatment, and outcome. J Thorac Dis. 2017;9(1):123–128. doi:10.21037/jtd.2017.01.25

73. Tay CK, Chua YC, Takano A, et al. Primary pulmonary lymphoepithelioma-like carcinoma in Singapore. Ann Thorac Med. 2018;13(1):30–35. doi:10.4103/atm.ATM_304_17

74. Huang CJ, Feng AC, Fang YF, et al. Multimodality treatment and long-term follow-up of the primary pulmonary lymphoepithelioma-like carcinoma. Clin Lung Cancer. 2012;13(5):359–362. doi:10.1016/j.cllc.2012.01.002

75. Chan AT, Teo PM, Lam KC, et al. Multimodality treatment of primary lymphoepithelioma-like carcinoma of the lung. Cancer. 1998;83(5):925–929. doi:10.1002/(SICI)1097-0142(19980901)83:5<925::AID-CNCR18>3.0.CO;2-X

76. Zhou N, Lin Y, Peng X, Wang Y, Wang Y. Thorough survey and analysis of pulmonary lymphoepithelioma-like carcinoma in Macau and multimodality treatment for advanced disease. Lung Cancer. 2019;138:116–123. doi:10.1016/j.lungcan.2019.10.004

77. Kim C, Rajan A, DeBrito PA, Giaccone G. Metastatic lymphoepithelioma-like carcinoma of the lung treated with nivolumab: a case report and focused review of literature. Transl Lung Cancer Res. 2016;5(6):720–726. doi:10.21037/tlcr.2016.11.06

78. Ho JC, Lam DC, Wong MK, Lam B, Ip MS, Lam WK. Capecitabine as salvage treatment for lymphoepithelioma-like carcinoma of lung. J Thorac Oncol. 2009;4(9):1174–1177. doi:10.1097/JTO.0b013e3181b28f15

79. Narayanan A, Knollmann FD, Walby JAS, Lim S, Gandara DR, Riess JW. EBV-positive primary pulmonary lymphoepithelioma-like carcinoma response to PD-L1 blockade. Clin Lung Cancer. 2019;20(3):e238–e241. doi:10.1016/j.cllc.2018.12.015

80. Darrason M, Martin A, Soussan M, et al. Immunotherapy for LELC: case report and a focused review. Clin Lung Cancer. 2019;20(3):e393–e401. doi:10.1016/j.cllc.2018.12.008

81. Kumar V, Dave V, Harris J, Huang Y. Response of advanced stage recurrent lymphoepithelioma-like carcinoma to nivolumab. Immunotherapy. 2017;9(12):955–961.

82. Qiu ZX, Zhou P, Wang K. Primary pulmonary lymphoepithelioma-like carcinoma response favorably to nivolumab: a case report. Oncol Targets Ther. 2019;12:8595–8600. doi:10.2147/OTT.S219512

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